The ultimate objective of this program project is to improve the outcome of patients with malignant gliomas. Current therapy fails because of regrowth of infiltrative tumor. Treatment toxicity is common. Viral- based gene therapy techniques may permit delivery, to large volumes of tumor-infiltrated brain, of cytotoxic agents specifically active against tumor cells. The other two projects and cores of this program project embrace design and preliminary testing, in cell culture and rodent models, of strategies attempting o kill tumor cells without injuring normal cells. This project will develop methods of delivering vector-based therapy to large volumes of tumor-infiltrated brain and assess the safety and efficacy of these therapies in controlled rodent trials using the D74 model. Primate toxicity studies, in collaboration with the New England Regional Primate Research Center, are designed to satisfy the requirements of the FDA and RAC. Human gene marking and dose escalating Phase I clinical trials will optimize delivery of gene therapy to resectable recurrent tumors and test its safety. Delivery methods to be studies include (a) target volume saturation by stereotactically directed interstitial injections of vector-producing cells, virus particles, and polymers of prodrug; (b) pharmacologic (RMP-7) or osmotic modification of the blood-brain barrier during intravascular delivery of vectors or drugs, and (c) injection of vectors into the cerebrospinal fluid. Gene therapy paradigms that demonstrate strong clinical potential in preliminary cell culture and animal studies will undergo further testing in controlled trials designed to mimic the anticipated conical scenario. Rodent malignant brain tumor studies will be performed using well defined criteria of response and toxicity. Toxicity endpoints will be established in studies on nonhuman primates. Trials in humans with malignant recurrent gliomas are gene marking and therapeutic. Tumor tissue obtained by resection of previously treated tumor will be analyzed for transgene expression, cellular response, and levels of active drug metabolites. Proposals for formal, large-scale trials of gene therapy techniques proving safe and efficacious in the Phase I/II trials will be made to the NABTT Consortium.